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A PDGFRα-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine.
Jun, Hyun Jung; Appleman, Vicky A; Wu, Hua-Jun; Rose, Christopher M; Pineda, Javier J; Yeo, Alan T; Delcuze, Bethany; Lee, Charlotte; Gyuris, Aron; Zhu, Haihao; Woolfenden, Steve; Bronisz, Agnieszka; Nakano, Ichiro; Chiocca, Ennio A; Bronson, Roderick T; Ligon, Keith L; Sarkaria, Jann N; Gygi, Steve P; Michor, Franziska; Mitchison, Timothy J; Charest, Al.
Afiliação
  • Jun HJ; Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
  • Appleman VA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
  • Wu HJ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Rose CM; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
  • Pineda JJ; Department of Cell Biology, Harvard Medical School, Boston, MA, 02215, USA.
  • Yeo AT; Department of Systems Biology, Harvard Medical School, Boston, MA, 02215, USA.
  • Delcuze B; Sackler School of Graduate Studies, Tufts University School of Medicine, Boston, MA, 02111, USA.
  • Lee C; Sackler School of Graduate Studies, Tufts University School of Medicine, Boston, MA, 02111, USA.
  • Gyuris A; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Zhu H; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.
  • Woolfenden S; Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA.
  • Bronisz A; Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, 02111, USA.
  • Nakano I; Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, 02111, USA.
  • Chiocca EA; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.
  • Bronson RT; Department of Neurosurgery and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35243, USA.
  • Ligon KL; Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.
  • Sarkaria JN; Rodent Histopathology Core, Dana-Farber/Harvard Cancer Center, Boston, MA, 02215, USA.
  • Gygi SP; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Michor F; Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 55902, USA.
  • Mitchison TJ; Department of Cell Biology, Harvard Medical School, Boston, MA, 02215, USA.
  • Charest A; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Nat Commun ; 9(1): 3116, 2018 08 06.
Article em En | MEDLINE | ID: mdl-30082792
ABSTRACT
Glioblastoma multiforme (GBM) is an aggressive primary brain cancer that includes focal amplification of PDGFRα and for which there are no effective therapies. Herein, we report the development of a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PDGFRα, and the analysis of GBM signaling pathways using proteomics. We discover the tubulin-binding protein Stathmin1 (STMN1) as a PDGFRα phospho-regulated target, and that this mis-regulation confers sensitivity to vinblastine (VB) cytotoxicity. Treatment of PDGFRα-positive mouse and a patient-derived xenograft (PDX) GBMs with VB in mice prolongs survival and is dependent on STMN1. Our work reveals a previously unconsidered link between PDGFRα activity and STMN1, and highlight an STMN1-dependent cytotoxic effect of VB in GBM.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Vimblastina / Neoplasias da Mama / Glioblastoma / Resistencia a Medicamentos Antineoplásicos / Receptor beta de Fator de Crescimento Derivado de Plaquetas / Estatmina Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Vimblastina / Neoplasias da Mama / Glioblastoma / Resistencia a Medicamentos Antineoplásicos / Receptor beta de Fator de Crescimento Derivado de Plaquetas / Estatmina Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Ano de publicação: 2018 Tipo de documento: Article